Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: design, synthesis, and evaluation as topically applied, dermal anti-scarring agents.
Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent.
Bailey
Simon
S
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. simon.bailey@pfizer.com
Fish
Paul V
PV
Billotte
Stephane
S
Bordner
Jon
J
Greiling
Doris
D
James
Kim
K
McElroy
Andrew
A
Mills
James E
JE
Reed
Charlotte
C
Webster
Robert
R
D000279:Administration, Cutaneous; D055395:Bone Morphogenetic Protein 1 / Q000737:chemistry*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002921:Cicatrix / Q000188:drug therapy*; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy*; D015195:Drug Design; D004817:Epidermis / Q000187:drug effects; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D010080:Oxazoles / Q000737:chemistry
D006877:Hydroxamic Acids; D010080:Oxazoles; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1